Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a hydroxyl group on a tyrosine residue located on a protein substrate. Since protein kinases play critical roles in various cellular activities, deregulation of protein kinase activity can lead to altered cellular properties, such as uncontrolled cell growth associated with cancer.
The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4(ErbB-4). Mutations affecting EGFR expression or activity could result in cancer.
Dysregulation of the epidermal growth factor receptor signal transduction pathway has been implicated in tumorigenesis and cancer progression thus making it a clinically relevant target for novel anticancer treatments. Several inhibitors of the epidermal growth factor receptor signaling pathway have demonstrated clinical efficacy in cancer treatment. Small molecules such as gefitinib, erlotinib and lapatinib, as well as anti-EGFR antibodies cetuximab, panitumumab and trastuzumab, have been approved for the treatment of EGFR-overexpressing lung cancers.
Because of the emerging disease-related roles of epidermal growth factor receptors, there is a continuing need for compounds which may be useful for treating and preventing a disease which responds to inhibition of epidermal growth factor receptor(s) and have at least one advantageous property selected from potency, stability, selectivity, toxicity, pharmacodynamics properties and pharmacokinetics properties as an alternative. In this regard, a novel class of epidermal growth factor receptor inhibitors is provided herein.